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BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?

As reported by Nature News and Forbes’ The Medicine Show  on July 20, dapagliflozin, a BMS-developed diabetes drug marketed with partner AstraZeneca, was given a “thumbs-down” by an FDA review panel on July 19. After the 9-6 final vote, panel members commented favorably on the drug’s new mechanism, but evidently felt that the safety profile could not be overlooked: the FDA committee meeting statement mentions increased risk of breast and bladder cancer, increased genital infections, and perhaps most seriously, potential for drug-induced liver injury (DILI).

Dapagliflozin has been one of the rising stars of the new class of Sodium-Glucose cotransporter 2 (SGLT2) inhibitors for diabetes treatment, whose development roster includes Johnson & Johnson, Astellas, Boehringer Ingelheim, Roche, GSK, and Lexicon (Note: see Nat. Rev. Drug Disc. 2010, 551 for a full recap).  The excitement behind these drugs comes from a relatively new idea for diabetes treatment: inhibition of the SGLT2 enzyme stops the kidney from reabsorbing sugar, leading to excretion of the excess glucose in the urine, which in turn lowers blood sugar. Dapagliflozin, like most SGLT2 inhibitors, is a glucose molecule with a large aromatic group attached to the carbon atom in the spot chemists call the anomeric position. Such so-called C-glycosides are thought to have improved staying power in the bloodstream relative to O-glycosides (where the linkage point is at an oxygen atom, a more common scenario in sugars), since they are less susceptible to enzymatic breakdown.

So, how do you improve these compounds? A paper Pfizer published last March (J. Med. Chem. 2011, 2952) may offer some hope.  Pfizer noted that some of the C-glycoside SGLT2 inhibitors gave a positive micronucleus test, indicating their potential to damage chromosomes. To work around this liability, their chemists  designed an analog of dapagliflozin where a second hydroxymethyl (CH2-OH) group is “tied” underneath the ring, forming a bicyclic compound that advantageously rigidifies the compound, increasing potency, while at the same time blocking a potential site of reactive metabolite formation (which might contribute to further DILI). The improved compound shows high potency for SGLT2 (~920 pm), a negative micronucleus test, and is now in Phase II  trials.

Want to hear more? The lead author of Pfizer’s paper, Dr. Vincent Mascitti, will speak about the study as part of the Organic Division program at the ACS National Meeting in Denver – Sunday, August 28, 8:00 AM-8:30AM, Four Seasons BR1.

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